CN105294795B - Nucleoside phosphoramidate derivative and its application - Google Patents

Nucleoside phosphoramidate derivative and its application Download PDF

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CN105294795B
CN105294795B CN201510799993.8A CN201510799993A CN105294795B CN 105294795 B CN105294795 B CN 105294795B CN 201510799993 A CN201510799993 A CN 201510799993A CN 105294795 B CN105294795 B CN 105294795B
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Abstract

The invention discloses a kind of novel nucleoside Phosphoramidate derivatives and its applications, are Formulas I compound represented or its pharmaceutically acceptable acid salt, solvate or hydrate, wherein R1For C1~4Alkyl or deuterated C1~4Alkyl；R2For the phenyl or naphthyl arbitrarily replaced, substituent group is selected from deuterium, C1~4Alkyl, C1~4Alkoxy；And R1And R2In at least contain a deuterium substituent group；R3For amino acid acyl or polypeptide acyl group.The compound of the present invention can be applied to treatment mammalian virus sexuality dye, especially in terms of infection with hepatitis C virus.

Description

Nucleoside phosphoramidate derivatives and uses thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel nucleoside phosphoramidate derivative, a pharmaceutically acceptable acid salt, a pharmaceutically acceptable solvate or hydrate, a preparation method thereof, a medicinal composition thereof and application thereof in preparing medicaments for treating mammal infectious diseases, and preventing or treating hepatitis C, liver cirrhosis and liver cancer.
Background
Hepatitis C Virus (HCV) infection is a worldwide health problem with diverse clinical manifestations ranging from mild to inflammatory to severe to cirrhosis, liver cancer. There are over 2 billion infected individuals worldwide, with at least 3 to 4 million people infected each year. Once infected, approximately 20% of people clear the virus, but the rest of the people may carry HCV for the rest of their lives. From 10% to 20% of chronically infected individuals eventually develop liver-destructive cirrhosis or cancer. Among the current therapeutic agents for HCV infection are recombinant interferon, therapy alone or in combination with the nucleoside analog ribavirin, and sofosbuvir marketed by gilder. Despite these existing technologies, there is still an urgent clinical need for a therapeutic agent for HCV infection with high bioavailability, good liver selectivity, and high drug efficacy.
Disclosure of Invention
The invention aims to provide a novel nucleoside phosphoramidate derivative, a pharmaceutically acceptable acid salt, a solvate or a hydrate with anti-hepatitis C activity.
It is another object of the present invention to provide a pharmaceutical composition comprising the above nucleoside phosphoramidate derivative, pharmaceutically acceptable acid salt, solvate or hydrate.
The third purpose of the invention is to provide the application of the nucleoside phosphoramidate derivative, the pharmaceutically acceptable acid salt, the solvate or the hydrate as the medicine for resisting the viral infection of mammals or preventing or treating diseases such as hepatitis C, liver cirrhosis, liver cancer and the like.
The object of the invention can be achieved by the following measures:
a nucleoside phosphoramidate derivative, such as a compound of formula I or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
wherein,
R1is C1～4Alkyl or deuterated C1～4An alkyl group;
R2is optionally substituted phenyl or naphthyl, and the substituent is selected from deuterium and C1～4Alkyl radical, C1～4An alkoxy group;
and R is1And R2Containing at least one deuterium substituent;
R3is amino acid acyl or polypeptide acyl.
In a preferred embodiment, R1Is methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl or deuterated isopropyl.
In a more preferred embodiment, R1is-CH3、-CH2CH3、-CH(CH3)2、-CD3(also known as deuterated methyl-d 3), -CD2CD3(also known as deuterated ethyl-d 5), -CH (CD)3)2(also known as deuterated isopropyl-d 6) or-CD (CD)3)2(also known as deuterated isopropyl-d 7).
In a preferred embodiment, R2Is phenyl or deuterated phenyl.
In a more preferred embodiment, R2is-C6H5or-C6D5(also known as deuterated phenyl-d 5).
In the compounds of the formula I according to the invention, R1And R2In which at least one deuterium atom is presentSubstituent group, means R1And R2At least one of the radicals selected is a deuterium-containing group, which may be R1Is a deuterium-containing group and R2Not being a deuterium containing group, may also be R2Is a deuterium-containing group and R1Not being a deuterium containing group, may also be R1And R2All contain deuterium groups.
In a preferred embodiment, R3Is natural amino acid acyl, non-natural amino acid acyl or dipeptide acyl.
In a more preferred embodiment, R3Is natural amino acid acyl.
In a more preferred embodiment, R3Is glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophanyl, tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, threonyl, cysteinyl, prolyl, histaminyl or arginyl.
In a more preferred embodiment, R1is-CD3、-CD2CD3、-CH(CH3)2、-CH(CD3)2or-CD (CD)3)2，R2is-C6H5or-C6D5，R3Is glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophanyl, tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, threonyl, cysteinyl, prolyl, histaminyl or arginyl.
In a particularly preferred embodiment of the invention, the compound of the invention, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, wherein the compound is selected from:
in an embodiment of the invention, the derivatives provided herein include enantiomers and racemates of the compounds of formula I.
In an embodiment of the invention, the derivatives described herein include compounds of formula I or pharmaceutically acceptable acid salts thereof, including but not limited to the salts of the compounds with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.
"C" in the present invention1～4Alkyl "refers to a straight or branched chain saturated hydrocarbon group containing 1,2, 3, or 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like.
In the present invention, deuterium is an isotope of hydrogen (H), also called deuterium, and the symbol of the element is generally D.
The term "deuterated" as used herein means that hydrogen (H) in the group is replaced by deuterium (D), and includes mono-substitution or multi-substitution of two or more. For example, "deuterated isopropyl" in the context of the present invention refers to isopropyl groups wherein one or more hydrogens (H) are replaced by deuterium (D), such as-CH (CD)3)2、-CH(CD3)(CH3)、-CH(CD3)2or-CD (CD)3)2And the like.
The term "optionally substituted" in the present invention means having a substituent or not having a substituent.
"C" in the present invention1～4Alkoxy "refers to a straight or branched chain alkyl-substituted oxy group containing 1,2, 3 or 4 carbon atoms, i.e." C1～4alkyl-O- ".
The "amino acid acyl group" in the present invention refers to a group (NH2-R-C (═ O) -) formed by the amino acid (NH2-R-C (═ O) -OH) in which the carboxyl group is deficient in — OH. The amino acids referred to herein include 20 natural amino acids, and also include various unnatural amino acids, for example: alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (gin), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His) and the like.
The "peptidyl group" in the present invention refers to a group formed by a carboxyl group (-C (═ O) -OH) in a polypeptide lacking-OH, and the polypeptide herein includes small molecule compounds formed by 2, 3 or 4 or more amino acids through peptide bonds, preferably dipeptides, including but not limited to glycylglycine, proglumide, alanyldipeptide and the like.
In a second aspect, the present invention provides a process for preparing a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, of a nucleoside phosphoramidate derivative as described above, comprising the steps of:
reacting the compound of formula II with the compound of formula III in the presence of a condensing agent or reacting the compound of formula II with the compound of formula IV, and then removing the amino protecting group to obtain the compound of formula I
Wherein R in the compounds of formula II, III and IV1、R2、R3As defined for the compounds of formula I, the condensing agent may be Carbonyldiimidazole (CDI), N, N ' -Diisopropylcarbodiimide (DIC), N, N ' -Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide hydrochloride (EDC. HCl), O- (7-azabenzotriazole) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium hexafluorophosphate (H)BTU), the Cbz group is a benzyloxycarbonyl protecting group protecting the amino group.
As a preferred embodiment, the present invention provides a process for preparing the above nucleoside phosphoramidate derivative compound of formula I or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, which comprises dissolving the compound of formula II or a salt thereof in an organic solvent, adding a base in portions under cooling, then reacting with the compound of formula IV, and removing the Cbz protecting group by catalytic hydrogenation to obtain the compound of formula I; or reacting the compound of formula III with a condensing agent, adding a base, reacting with an organic solvent of a compound of formula II or a salt thereof, and removing the Cbz protecting group by catalytic hydrogenation to obtain the compound of formula I, which can be further purified by a conventional method such as recrystallization, column chromatography, etc., if necessary. Here, the base may be an inorganic base or an organic base, and may be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or N, N-diisopropylethylamine, etc. Salifying the compound of the formula I and an organic solvent solution or an aqueous solution of an acid according to a proportion to obtain an acid salt of the compound of the formula I.
In particular, for the present invention, R's such as MJ10807, MJ10808, MJ10810, MJ10811, MJ10813, MJ10814, MJ10815, MJ10816, MJ10817, MJ10818, MJ10819, MJ10820, etc. are mentioned3Adding corresponding side chain protection to a compound with an additional easily-reactive functional group in the group, wherein the side chain protection can be benzyloxycarbonyl, benzyl and the like, and adding a deprotection step after the condensation reaction.
In a third aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, of each of the nucleoside phosphoramidate derivatives, wherein the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or diluent, and wherein the pharmaceutical composition may further comprise other active ingredients, to form a combination or synergistic composition. The pharmaceutical composition can be administered by intravenous injection, by injection into tissue, intraperitoneal administration, oral administration or intranasal administration. The pharmaceutical composition may have a form selected from the group consisting of a solution, a dispersion, a suspension, a powder, a capsule, a tablet, a pill, an extended release capsule, an extended release tablet, and an extended release pill. The administration dosage of the pharmaceutical composition is 5-5000 mg/day.
In a fourth aspect, the invention provides the nucleoside phosphoramidate derivative as shown in formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, which can be used for preparing a medicament for preventing or treating viral infection of mammals, in particular for preparing a medicament for preventing or treating hepatitis c, liver cirrhosis or liver cancer of mammals. Mammals in the present invention include, but are not limited to, humans, tigers, wolves, mice, deer, minks, monkeys, tapirs, lazy trees, zebras, dogs, rabbits, foxes, bears, elephants, leopards, musks, lions, pandas, pigs, antelopes, reindeer, koala, rhinoceros, lynx, pangolins, giraffes, pandas, ant animals, orangutans, sea cows, otters, prodigies, dolphins, elephants, vases, hedgehogs, arctic foxes, polar bears, kangaroos, cheilognos, hippopotamus, whales, weasels, and the like.
Compared with the prior art, the novel nucleoside phosphoramidate derivative has remarkable anti-HCV activity, and the concentration of a key index liver active metabolite of the anti-HCV activity is even obviously higher than that of sofosbuvir.
Drawings
FIG. 1 concentration of the liver active metabolite GS-461203 (ng/g) following gavage administration of 20mg/kg of a compound of the invention and sofosbuvir to SD rats.
Detailed Description
The following examples are provided to illustrate embodiments of the present invention, and it will be apparent to those skilled in the art that modifications of the embodiments of the present invention in light of the above teachings and known in the art are within the scope of the present invention.
The sources of the compound starting materials used in the examples are: all reagents and starting materials were commercially available and the compound of formula II was synthesized by the method described in reference to J.org.chem.2011,76, 8311-.
NMR data were collected and processed by a Bruker AV-300 NMR spectrometer.
Example 1 Synthesis of MJ10803
(1) Synthesis of intermediate M811
Dissolving 4-nitrobenzene dichlorophosphoric acid (S1,25.6g and 0.1mol) serving as a starting material in 150ml of anhydrous dichloromethane, cooling to-60 ℃, slowly dropwise adding 45ml of anhydrous dichloromethane solution of deuterated phenol-d 5(9.9g and 0.1mol) and triethylamine (15ml and 0.11mol) while stirring, naturally heating to-5 ℃ after dropwise adding, and reacting for 3 hours. Alanine isopropyl ester hydrochloride (16.8g,0.11mol) was added to the reaction mixture, stirred at 0 ℃ for 30min, triethylamine (28.6ml,0.21mol) was added dropwise, the reaction was carried out at 5 ℃ for 3h, insoluble matter was filtered, the reaction mixture was concentrated to obtain an oil, and silica gel column chromatography was carried out to obtain 13.7g of a mixture of M811 and M811D as a white solid, with a mixture yield of 33.6%.
Dissolving the mixture with 50ml diisopropyl ether, stirring and cooling to 5 ℃, stirring and preserving heat for 22h, further cooling to-10 ℃, stirring and cooling for 44h, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white solid.
Recrystallizing the white solid with 40ml diisopropyl ether, slowly cooling to the generation of the white solid, further slowly cooling to-10 ℃,preserving the heat for 16h, filtering and drying a filter cake to obtain 8.1g of white solid and an intermediate M811 with the yield of 20.3 percent. MS (m/z): 414.2[ M +1 ]]+。
(2) Synthesis of intermediate M812
The nucleoside (S2,260mg,1mmol) was added to the reaction flask, dissolved in 6ml of dry Tetrahydrofuran (THF), added dropwise to 2.5ml (2.5mmol) of a 1M solution of tert-butylmagnesium chloride in THF under ice-cooling and nitrogen-blanketing, and stirred at room temperature for 30 min. Intermediate M811(537mg,1.3mmol) was dissolved in 6ml of tetrahydrofuran, added dropwise to the reaction mixture, and reacted at room temperature for 24 hours. The reaction was quenched with 10ml of saturated ammonium chloride under ice bath, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel chromatography to obtain the desired compound, intermediate M812(135mg), in 25.4% yield. MS (m/z): 535.3[ M +1 ]]+。
(3) Synthesis of intermediate M813
Dissolving Cbz-Val-OH (S3,251mg,1mmol) with 2ml of N, N-Dimethylformamide (DMF), cooling to-5 deg.C, adding DIC (63.1mg,0.5mmol) under stirring, reacting at room temperature for 30min, further cooling to-5 deg.C, sequentially adding 2ml of DMF solution of intermediate M812(267mg,0.5mmol), triethylamine (60.7mg,0.6mmol), catalytic amount of 4-Dimethylaminopyridine (DMAP), reacting at room temperature for 4h, pouring into 10ml of water after reaction, extracting with 10ml of ethyl acetate for 3 times, combining organic layers, drying with anhydrous sodium sulfate, spin-drying solvent to obtain yellow solid, separating by silica gel column chromatography to obtain white-like powder (intermediate M813,205mg, yield 53.4%. MS (M/z): 768.3[ M +1 ]]+。
(4) Synthesis of MJ10803
Intermediate M813(383mg,0.5mmol) was dissolved in 3ml of methanol, 5% Pd/C was added in 360mg, and the reaction was carried out under hydrogen for 20min, after completion of the reaction, Pd/C was filtered off, the solvent was spun off from the filtrate, and the filtrate was separated by silica gel column chromatography to obtain 153mg of white powder (MJ10803) with a yield of 48.3%. MS (m/z): 634.3[ M +1 ]]+；1H-NMR(DMSO-d6)δ：0.88-1.36(m,18H),1.86-1.93(m,1H),3.22-3.26(m,1H),3.76-3.83(m,2H),4.00-4.06(m,1H),4.21-4.31(m,2H),4.81-4.89(m,1H),5.33-5.51(m,1H),5.64-5.66(m,2H),6.03-6.11(m,2H),7.71-7.72(m,1H),7.96(s,1H)。
Example 2 Synthesis of MJ10823
(1) Synthesis of intermediate M821
Alanine deuterated isopropyl ester hydrochloride-d 6 was prepared from alanine by acid-catalyzed reaction in deuterated isopropyl alcohol-d 6.
Dissolving 4-nitrobenzene dichlorophosphoric acid (S1,25.6g and 0.1mol) serving as a starting material in 150ml of anhydrous dichloromethane, cooling to-60 ℃, slowly dropwise adding 45ml of anhydrous dichloromethane solution of deuterated phenol-d 5(9.9g and 0.1mol) and triethylamine (15ml and 0.11mol) while stirring, naturally heating to-5 ℃ after dropwise adding, and reacting for 3 hours. Alanine deuterated isopropyl ester hydrochloride-d 6(17.4g,0.11mol) is added into the reaction solution, stirred for 30min at 0 ℃, triethylamine (28.6ml,0.21mol) is added dropwise, reaction is carried out for 3h at 5 ℃, insoluble substances are filtered, the reaction solution is concentrated to obtain oily substances, and silica gel column chromatography is carried out to obtain 12.9g of a mixture of white solids M821 and M821D, wherein the yield of the mixture is 30.8%.
Dissolving the mixture with 50ml diisopropyl ether, stirring and cooling to 5 ℃, stirring and preserving heat for 22h, further cooling to-10 ℃, stirring and cooling for 44h, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white solid.
Recrystallizing the white solid with 40ml diisopropyl ether, slowly cooling to generate the white solid, further slowly cooling to-10 ℃, preserving heat for 16h, filtering, and drying the filter cake to obtain 7.6g of the white solid and the intermediate M821 with the yield of 18.1%. MS (m/z): 420.2[ M +1 ]]+。
(2) Synthesis of intermediate M822
The intermediate M821 was used as a starting material to prepare the objective compound in the same manner as in the intermediate M812 of example 1. MS (m/z): 541.3[ M +1 ]]+。
(3) Synthesis of intermediate M823
The objective compound was obtained in the same manner as in intermediate M813 of example 1, starting from intermediate M822. MS (m/z): 774.3[ M +1 ]]+。
(4) Synthesis of MJ10823
The intermediate M823 was used as a starting material to prepare the target compound in the same manner as MJ10803 in example 1. MS (m/z): 640.3[ M +1 ]]+；1H-NMR(DMSO-d6)δ：0.86-1.28(m,12H),1.83-1.90(m,1H),3.21-3.24(m,1H),3.77-3.82(m,2H),3.98-4.05(m,1H),4.23-4.28(m,2H),4.62(s,1H),5.32-5.52(m,1H),5.62-5.65(m,2H),6.01-6.09(m,2H),7.69-7.73(m,1H),7.93(s,1H)。
Example 3 Synthesis of MJ10863
The objective compound was obtained in the same manner as in example 2, using alanine deuterated isopropyl ester hydrochloride-d 7 as a starting material. MS (m/z): 641.3[ M +1 ]]+。
Alanine deuterated isopropyl ester hydrochloride-d 7 was prepared from alanine by acid-catalyzed reaction in deuterated isopropyl alcohol-d 8.
Example 4 Synthesis of MJ10843
The target compound was prepared in the same manner as in example 1, using alanine deuterated isopropyl ester hydrochloride-d 6 and phenol as starting materials. MS (m/z): 635.3[ M +1 ]]+；1H-NMR(DMSO-d6)δ：0.89-1.29(m,12H),1.85-1.93(m,1H),3.23-3.25(m,1H),3.78-3.83(m,2H),4.00-4.08(m,1H),4.19-4.30(m,2H),4.58(s,1H),5.31-5.50(m,1H),5.63-5.68(m,2H),6.01-6.11(m,2H),7.15-7.21(m,3H),7.34-7.41(m,2H),7.69-7.73(m,1H),7.99(s,1H)。
Alanine deuterated isopropyl ester hydrochloride-d 6 was prepared from alanine by acid-catalyzed reaction in deuterated isopropyl alcohol-d 6.
Example 5 Synthesis of MJ10883
Taking alanine deuterated isopropyl ester hydrochloride-d 7 and phenol as raw materials,the same procedure as in example 1 was repeated to give the titled compound. MS (m/z): 636.3[ M +1]+。
Alanine deuterated isopropyl ester hydrochloride-d 7 was prepared from alanine by acid-catalyzed reaction in deuterated isopropyl alcohol-d 8.
EXAMPLE 6 Synthesis of other Compounds
The synthesis of the compounds in the following table is the same as that in example 1 MJ10803, except that different starting materials and different corresponding intermediates are adopted, and the condensation reaction and deprotection are carried out with different amino acids, so as to obtain the target product.
Example 7 assay of GS-461203 content in the liver following intragastric administration of test Compounds to rats
GS-461203 is an active metabolite of the anti-hepatitis C drug sofosbuvir (sofosbuvir) formed in vivo, which can be incorporated into hepatitis C virus RNA by NS5B polymerase to exert antiviral action. The content of GS-461203 in the liver after administration can reflect the strength of the anti-hepatitis C virus effect of the compound.
108 SD rats, divided into 6 groups on average, are respectively gavaged with a dose of 20mg/kg for administration of sofosbuvir and test solutions of patent compounds, and are killed by inhaling carbon dioxide at 0.5, 1,2, 4, 8 and 24 hours after administration (3 animals/time/group), and the liver is perfused with ice-bath physiological saline, then a proper amount of liver sample is taken, and immediately placed in an environment of-80 ℃.
Adding an ice bath 70% methanol aqueous solution (containing EDTA and the like) into a rat liver sample, homogenizing, centrifuging, taking a proper amount of supernatant, volatilizing, and dissolving by using an acetonitrile aqueous solution containing 0.1% formic acid to obtain a test solution.
The content of GS-461203 in the sample was determined by LC/MS/MS method, and the liver exposure (AUC) was calculated, and the results are shown in Table 1.
TABLE 1 Exposure of GS-461203 in the liver after gavage administration in rats (AUC)
Compound (I) sofosbuvir MJ10803 MJ10823 MJ10843 MJ10863 MJ10883
Dosage (mg/kg) 20 20 20 20 20 20
AUC0-t(μg.h/g) 15.4 30.4 28.7 31.2 33.8 30.8
The GS-461203 AUC of the patent compound liver was higher than that of sofosbuvir, with MJ10803, MJ10823, MJ10843, MJ10863 and MJ10883 groups significantly higher than that of sofosbuvir.
Example 8 solubility determination
Sofosbuvir cannot be salified under acidic and alkaline conditions, and hardly dissolves in neutral aqueous solution, while the proprietary compound can be salified with acid, so that the solubility of the proprietary compound in water is increased, and the proprietary compound is convenient to prepare.
Preparation of the hydrochloride salt of the patented compound: dissolving free base of the patent compound with ethyl acetate, dropwise adding a hydrogen chloride ethyl acetate solution, stirring for 10min, adding petroleum ether, precipitating a precipitate, washing the precipitate with petroleum ether for 3 times, and removing the solvent under reduced pressure to obtain the hydrochloride of the product.
Preparation of reference standard solution: the sofosbuvir and the hydrochloride of the patent compound were dissolved in methanol to prepare 0.5mg/ml solutions.
Dissolving the sample to be tested with water until precipitate is separated out at the bottom, filtering, measuring the absorption coefficient by ultraviolet spectrophotometry, calculating the concentration of the sample, and testing to show that the solubility of the patent compound is more than 15mg/ml, and the results of MJ10803, MJ10823, MJ10843, MJ10863 and MJ10883 are shown in Table 2.
TABLE 2 solubility of the compounds of the invention
Compound (I) sofosbuvir MJ10803 hydrochloride salt MJ10823 hydrochloride salt
Solubility in water <2mg/ml >15mg/ml >15mg/ml
Compound (I) MJ10843 hydrochloride salt MJ10863 hydrochloride salt MJ10883 hydrochloride salt
Solubility in water >15mg/ml >15mg/ml >15mg/ml

Claims (9)

1. A compound of formula I or a pharmaceutically acceptable acid salt thereof:
wherein,
R1is C1～4Alkyl or deuterated C1～4An alkyl group;
R2is optionally substituted phenyl or naphthyl, and the substituent is selected from deuterium and C1～4Alkyl radical、C1～4An alkoxy group;
and R is1And R2Containing at least one deuterium substituent;
R3is natural amino acid acyl.
2. A compound according to claim 1, or a pharmaceutically acceptable acid salt thereof, wherein R1Is methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl or deuterated isopropyl, R2Is phenyl or deuterated phenyl, and R1And R2Containing at least one deuterium substituent.
3. A compound according to claim 2, or a pharmaceutically acceptable acid salt thereof, wherein R1is-CH3、-CH2CH3、-CH(CH3)2、-CD3、-CD2CD3、-CH(CD3)2or-CD (CD)3)2，R2is-C6H5or-C6D5And R is1And R2Containing at least one deuterium substituent.
4. A compound according to claim 3, or a pharmaceutically acceptable acid salt thereof, wherein R3Is glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophanyl, tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, threonyl, cysteinyl, prolyl, histaminyl or arginyl.
5. A compound according to claim 1, or a pharmaceutically acceptable acid salt thereof, wherein R1is-CD3、-CD2CD3、-CH(CH3)2、-CH(CD3)2or-CD (CD)3)2，R2is-C6H5or-C6D5，R3Is glycyl, alanyl, valyl, leucyl, isoleucyl, phenylalanyl, tryptophanyl, tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, threonyl, cysteinyl, prolyl, histaminyl or arginyl.
6. A compound according to claim 1, or a pharmaceutically acceptable acid salt thereof, wherein the compound is selected from:
7. a pharmaceutical composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable acid salt thereof.
8. Use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable acid salt thereof, in the manufacture of a medicament for the prevention or treatment of a viral infection in a mammal.
9. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable acid salt thereof in the preparation of a medicament for preventing or treating hepatitis c, cirrhosis or liver cancer in a mammal.
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